HealthyPhase 4NCT03435055

Network-Level Effects of Nitrous Oxide in the Human Brain

A Phase 4 study testing Nitrous Oxide Gas for Inhalation in people with Healthy, run by University of Michigan at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this study is to understand how a commonly used drug, nitrous oxide, acts on the brain to reduce pain. Nitrous oxide is commonly used in anesthesiology but there is limited knowledge on how this drug affects functional networks in the brain. Read more about this study

Who is it for?: Ages 21 to 40 yearsHealthy volunteers can take part
Conditions the study is for: Healthy
What is being tested?: Nitrous Oxide Gas for Inhalation
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 21 participants
Where: 1 siteUnited States
Study dates: 21 Jul 2017to 11 Oct 2019
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 21 to 40 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

Body mass index <30
Must be right-handed
Must be capable of giving written informed consent

Who cannot join

History of obstructive sleep apnea;
History of a difficult airway with a previous anesthetic
Gastroesophageal reflux;
Hypertension or other cardiovascular abnormalities;
Pulmonary hypertension;
History of recreational drug use;

Show all 17Show fewer

History of chronic alcohol abuse
Having any chronic medical illness involving pain;
History of major depression;
History of psychosis or bipolar disorder;
History of methylenetetrahydrofolate reductase deficiency;
History of a known hypersensitivity to ketamine, midazolam, Zofran, labetalol or glycopyrrolate
History of seizures or other neurologic disorders;
Pregnant or nursing mothers;
Tattoos on the head or neck region - all other tattoos are subject to determination by investigators;
Contraindications to neuroimaging methods;
Any impairment, activity or situation that in the judgment of the Study Coordinator or Principal Investigators would prevent satisfactory completion of the study protocol.

Trial locations and contacts

1 site in 1 country.

United States1 site

Michigan Medicine - University of Michigan
Ann Arbor, Michigan, 48109

Other trials in United States

About this study

Read the detailed description

The objective of this study is to identify the network transformations that account for the analgesic effects of nitrous oxide. Our hypothesis is that analgesic doses of nitrous oxide increase network efficiency and disrupt normal pain processingOur approach is to administer subanesthetic nitrous oxide during the acquisition of fMRI (functional magnetic resonance imaging) and EEG (electroencephalogram).

Conditions: Healthy
Being tested: Nitrous Oxide Gas for Inhalation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Nitrous Oxide Gas for InhalationDrug
Each volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanesthetic levels (35% inhaled concentration) over 40 minutes.

Study groups in NCT03435055
Study group	Role	What they receive
Nitrous Oxide - inhaled	Experimental	Each volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 40 minutes. Receives: Drug: Nitrous Oxide Gas for Inhalation

What is being measured

The primary outcome is the main question the study is designed to answer.

Functional Connectivity During Nitrous Oxide
Functional connectivity measures will be assessed at rest (baseline) and during sub anesthetic dose nitrous oxide (nitrous oxide). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions.
Measured: Baseline to 50 minutes
Functional Connectivity Associated With Tonic Stimulus
Functional connectivity measures will be assessed at rest (baseline) and during a tonic cuff stimulus (6-minutes). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions.
Measured: Baseline to 50 minutes

Secondary outcomes (2)

Tonic Stimulus Intensity During Nitrous Oxide
Participants will receive a tonic (6 minutes) pressure applied to the lower leg at baseline and under subanesthetic dose of nitrous oxide (35% inhaled concentration). Following each pressure stimulus, participants will rate the pain intensity of the tonic stimulus (0 ="no pain", 10= "worst pain imaginable", Visual Analog Scale, e.g pain intensity).
Measured: Baseline to 50 minutes
Spectral Power of Sub-anesthetic Dose of Nitrous Oxide
Brain imaging data were obtained from functional magnetic resonance imaging (fMRI) data recorded simultaneously with electroencephalography (EEG) data at baseline and under a sub-anesthetic dose of nitrous oxide. Spectral data were averaged from EEG data at all electrodes collected during the baseline and sub-anesthetic dose (35%) of nitrous oxide to observe changes in spectral power. The EEG power spectrum was divided into three frequency bands: Delta = 1-3 Hz; Theta = 4-7 Hz; and Alpha = 8 - 13 Hz
Measured: Baseline to 50 minutes

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

21 Jul 201711 Oct 2019

First posted15 Feb 2018
Study start21 Jul 2017
Primary completion11 Oct 2019
Study completion11 Oct 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for HealthyStudies of the same condition, open and under way.
More trials run by University of MichiganThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Basic science
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 21 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03435055
Sponsor's protocol ID: HUM00096321
Status last verified: Nov 2021
First submitted: 25 Jan 2018
Last updated: 30 Nov 2021
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Dai R, Larkin TE, Huang Z, Tarnal V, Picton P, Vlisides PE, Janke E, McKinney A, Hudetz AG, Harris RE, Mashour GA. Classical and non-classical psychedelic drugs induce common network changes in human cortex. Neuroimage. 2023 Jun;273:120097. doi: 10.1016/j.neuroimage.2023.120097. Epub 2023 Apr 7.
PubMed 37031827

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 30 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Network-Level Effects of Nitrous Oxide in the Human Brain
ClinicalTrials.gov ID: NCT03435055
Acronym / sponsor ID: HUM00096321
Conditions: Healthy
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 21 participants (actual)
Lead sponsor: University of MichiganUniversity, hospital or other
Study start: 21 Jul 2017 (actual)
Primary completion: 11 Oct 2019 (actual)
Study completion: 11 Oct 2019 (actual)
First posted: 15 Feb 2018 (actual)
Results: Posted 9 Jul 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Nitrous Oxide - inhaled	Experimental	Drug: Nitrous Oxide Gas for InhalationEach volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 40 minutes.

Who may qualify

Ages: 21 to 40 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (3 listed)

Body mass index <30
Must be right-handed
Must be capable of giving written informed consent

Key exclusion criteria (17 listed)

History of obstructive sleep apnea;
History of a difficult airway with a previous anesthetic
Gastroesophageal reflux;
Hypertension or other cardiovascular abnormalities;
Pulmonary hypertension;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Nitrous Oxide Gas for InhalationEach volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanesthetic levels (35% inhaled concentration) over 40 minutes.	Drug	Nitrous Oxide - inhaled

Primary outcome

Functional Connectivity During Nitrous Oxide
Time frame: Baseline to 50 minutes
Functional connectivity measures will be assessed at rest (baseline) and during sub anesthetic dose nitrous oxide (nitrous oxide). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions.
Functional Connectivity Associated With Tonic Stimulus
Time frame: Baseline to 50 minutes
Functional connectivity measures will be assessed at rest (baseline) and during a tonic cuff stimulus (6-minutes). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions.

2 secondary outcomes

Tonic Stimulus Intensity During Nitrous Oxide
Time frame: Baseline to 50 minutes
Spectral Power of Sub-anesthetic Dose of Nitrous Oxide
Time frame: Baseline to 50 minutes

Results and safety

Results posted to the registry on 9 Jul 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Nitrous Oxide - Inhaled	21	19

Primary outcome: Functional Connectivity During Nitrous Oxide

Time frame: Baseline to 50 minutes. Mean (Standard Deviation). Unit: Fisher's r transformed z score

Measure	Pre-Nitrous n = 16	Nitrous Oxide - Subanesthetic Dose n = 16
L superior frontal gyrus	0.1123 (0.0639)	0.0358 (0.0620)
R superior frontal gyrus	0.1492 (0.1179)	0.0394 (0.0950)

Pre-Nitrous vs Nitrous Oxide - Subanesthetic Dose: p = 0.001, t-test, 2 sided

Population analysed: Three participants had missing data because they did not complete the full scanning protocol.

Primary outcome: Functional Connectivity Associated With Tonic Stimulus

Time frame: Baseline to 50 minutes. Mean (Standard Deviation). Unit: Z score

Measure	Pre-Tonic Cuff n = 19	Tonic Cuff Stimulus n = 19
Value	-0.0509 (0.0822)	0.0486 (0.1001)

Pre-Tonic Cuff vs Tonic Cuff Stimulus: p = 0.006, t-test, 2 sided

Population analysed: Number of participants scanned.

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data was collected for 24 hours.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Nitrous Oxide - Inhaled	0 of 19 (0%)	2 of 19 (10.5%)	0 of 19

Limitations and caveats (from the sponsor): Data for the Spectral Power of Sub-anesthetic Dose of Nitrous Oxide outcome measure will be analyzed within the coming year and the ClinicalTrials.gov record will be updated at that time.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Nov 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 37031827Dai R, Larkin TE, Huang Z, Tarnal V, Picton P, Vlisides PE, Janke E, McKinney A, Hudetz AG, Harris RE, Mashour GA. Classical and non-classical psychedelic drugs induce common network changes in human cortex. Neuroimage. 2023 Jun;273:120097. doi: 10.1016/j.neuroimage.2023.120097. Epub 2023 Apr 7.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Richard Harris, PhD principal investigator

Associate Professor of Anesthesiology and Associate Professor of Internal Medicine

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Nitrous Oxide Gas for Inhalation in people with Healthy, run by University of Michigan at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Jul 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Functional Connectivity During Nitrous Oxide (time frame: Baseline to 50 minutes). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03435055, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2021.